WO2014020553A1

WO2014020553A1 - Salts of pralatrexate

Info

Publication number: WO2014020553A1
Application number: PCT/IB2013/056285
Authority: WO
Inventors: Saswata Lahiri; Nitin Gupta; Hemant Kumar Singh
Original assignee: Fresenius Kabi Oncology Ltd.
Priority date: 2012-08-03
Filing date: 2013-07-31
Publication date: 2014-02-06

Abstract

The present invention provides salts of Pralatrexate, in particular, sodium, lithium and potassium salts and their polymorphic forms, process for the preparation thereof, pharmaceutical compositions comprising these salts and at least one pharmaceutically acceptable excipient, and the use of pharmaceutical composition for the treatment of conditions related to human tumors.

Description

SALTS OF PRALATREXATE

FIELD OF THE INVENTION

The present invention relates to salts of Pralatrexate and their polymorphic forms, process for the preparation thereof, pharmaceutical compositions thereof and the use of pharmaceutical composition for the treatment of conditions related to human tumors.

BACKGROUND OF THE INVENTION

Pralatrexate chemically known as "(25)-2-[[4-[(lR5)-l-[(2,4-diaminopteridin-6- yl)methyl]but-3-ynyl]benzoyl]- amino] pentanedioic acid" also known as "10-Propargyl- 10-deazaminopterin" or "PDX" is a compound which has been tested and found useful in the treatment of cancer. In its racemic form, 25)-2-[[4-[(lR5)-l-[(2,4-diaminopteridin-6- yl)methyl]but-3-ynyl]benzoyl]amino]- pentanedioic acid has been approved by the U.S. Food and Drug Administration (FDA) as a treatment for relapsed and refractory peripheral T-cell lymphoma.

Pralatrexate molecule (I) was first disclosed in Journal of Medicinal Chemistry. 36: 2228- 2231 (1993) by DeGraw et al, and subsequently in US 5374726, US 5354741 and US 6028071.

Tiseni et al., in International Application Publication No. WO 2012/061469 discloses crystalline forms A, B, and C of Pralatrexate. The publication also discloses amorphous form of Pralatrexate.

Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule, like Pralatrexate, may give rise to a variety of polymorphic forms having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, infrared absorption fingerprint, Raman spectrum, density, crystal group, and solid state NMR spectrum.

One polymorphic form may give rise to thermal behavior different from that of another polymorphic form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis ("TGA"), and differential scanning calorimetry ("DSC"), which have been used to distinguish polymorphic forms. The difference in the physical properties of different polymorphic forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other polymorphic forms of the same compound or complex.

The discovery of new polymorphic forms and solvates of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. Therefore, there is a need for additional polymorphic forms of Pralatrexate.

It is also important that the processes for the preparation of the salts in different polymorphic forms be robust and reproducible, so that the processes are easily scaled up in the plant.

The present invention addresses a need in the art by providing salts of Pralatrexate in different polymorphic forms, which are believed to provide significant advantages for making pharmaceutical compositions, as compared to the polymorphic form of Pralatrexate free acid disclosed in the prior art.

As is well known to the skilled artisan, variations in the salt form and/or crystal structure of a pharmaceutical drug substance often affect the dissolution rate (which may affect bioavailability, etc.), manufacturability (e.g., ease of handling, ability to consistently prepare doses of known strength) and stability (e.g., thermal stability, shelf life, etc.) of a pharmaceutical drug product. Salts of Pralatrexate and their Polymorphic forms, such as the crystalline forms and amorphous form of the present invention are believed to provide advantages over Pralatrexate free acid disclosed in the prior art.

Pralatrexate has been described as the free acid of formula (I) in US 6028071, as a treatment for relapsed and refractory peripheral T-cell lymphoma.

The present invention provides salts of Pralatrexate. The present invention also provides processes for their preparation, which is robust and reproducible. The present invention further provides pharmaceutical compositions comprising said salts of Pralatrexate and at least one pharmaceutically acceptable excipient. The present invention still further provides a method for treatment of tumors using pharmaceutical composition comprising salts of Pralatrexate.

SUMMARY OF THE INVENTION

First aspect of the present invention provides a salt of Pralatrexate of formula (II), wherein M is an alkali or alkaline earth metal.

variation, the salt is represented by Formula (IF),

( (ΙΓ)

In another variation, the salt of Formula (IF) is Crystalline.

In yet another variation, the salt of Formula (IF) is Amorphous.

In a further variation, the salt is represented by formula (Ila)

(I la)

In a yet further variation, the salt is represented by the formula (lib)

(lib) Second aspect of the present invention provides a process for producing a salt of formula (II) comprising the steps of

a) reacting Pralatrexate of formula (I) with a source of alkali or alkaline earth metal in presence of a suitable solvent to obtain a reaction mixture;.

b) stirring the reaction mixture of step (a) and;

c) isolating the salt from the reaction mixture.

In one variation, step (a) is followed by addition of a second suitable solvent.

In another variation, step (b) is followed by cooling.

In yet another variation, salt of step (c) is isolated by freeze drying or filtration.

In a still further variation, the compound of Formula (II) is converted to a compound of Formula (I).

Third aspect of the present invention provides pharmaceutical composition comprising salt of formula (II) and at least one pharmaceutically acceptable excipient.

Fourth aspect of the present invention provides a method for treatment of tumors using pharmaceutical composition comprising salt of formula (II). BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 depicts the X-ray Powder diffractogram of Pralatrexate.

Figure 2 depicts the X-ray Powder diffractogram of crystalline Pralatrexate disodium of formula (IF).

Figure 3 depicts the X-ray Powder diffractogram of amorphous Pralatrexate disodium of formula (IF).

Figure 4 depicts the X-ray Powder diffractogram of amorphous Pralatrexate dilithium of formula (Ila).

Figure 5 depicts the X-ray Powder diffractogram of amorphous Pralatrexate dipotassium of formula (lib).

Figure 6 depicts the DSC thermogram of amorphous Pralatrexate dilithium of formula (Ila).

Figure 7 depicts the TGA profile of amorphous Pralatrexate dilithium of formula (Ila). Figure 8 depicts the DSC thermogram of amorphous Pralatrexate dipotassium of formula (lib).

Figure 9 depicts the TGA profile of amorphous Pralatrexate dipotassium of formula (lib). DETAILED DESCRIPTION OF THE INVENTION

The alkali metal in the compound of formula II may be selected from the group comprising of sodium, lithium, potassium and the like.

The alkaline -earth metal in the compound of formula II may be selected from the group comprising of calcium, magnesium and the like.

The salt of Formula (II) may be characterized using various techniques, which are well known to those of ordinary skill in the art. Examples of characterization methods include, but are not limited to, single crystal X-ray diffraction, powder X-ray diffraction (PXRD), simulated powder X-ray patterns, differential scanning calorimetry (DSC), solid-state ¹³C- NMR, Raman spectroscopy, infrared spectroscopy, moisture sorption isotherms, thermal gravimetric analysis (TGA), and hot stage techniques.

The crystalline salt of Formula (IF) may be characterized as having powder X-ray diffraction pattern peaks of 2Θ at 4.32, 6.08, 6.81, 9.93, 17.4, 23.13, 25.48, 27.82 ± 0.2°. The crystalline salt of formula (IF) may be characterized by having a powder X-ray diffraction pattern substantially as shown in Figure 2. The crystalline polymorphic form of formula (IF) may be further characterized by having water content between about 1% and about 20 %.

The amorphous salt of formula (IF) may be characterized by powder X-ray diffraction of one broad halo at 2Θ of about 26°. The amorphous polymorphic form of salt of formula (IF) may be characterized by having a powder X-ray diffraction pattern substantially as shown in Figure 3. The amorphous form may be further characterized by having water content between about 1% and about 20 %.

The amorphous salt of formula (Ila) may be characterized by having a powder X-ray diffraction pattern substantially as shown in Figure 4. The amorphous form may be further characterized by having water content between about 1% and about 20 %. The amorphous salt of formula (Ila) may be further characterized by having a DSC thermogram substantially as shown in Figure 6. The amorphous salt of formula (Ila) may be still further characterized by having a TGA profile substantially as shown in Figure 7. The amorphous form may be further characterized by having water content between about 1% and about 20 %.

The amorphous salt of formula (lib) may be characterized by having a powder X-ray diffraction pattern substantially as shown in Figure 5. The amorphous form may be further characterized by having water content between about 1% and about 20 %. The amorphous salt of formula (lib) may be further characterized by having a DSC thermogram substantially as shown in Figure 8. The amorphous salt of formula (lib) may be still further characterized by having a TGA Profile substantially as shown in Figure 9. The amorphous form may be further characterized by having water content between about 1% and about 20 %.

Furthermore, the present salt forms may be anhydrous or contain solvent(s), such as water. In some embodiments, the present salt forms comprise solvate, such as hydrate. Pralatrexate used as starting material may be obtained by any of the methods known in the art including as described in Example- 1.

The source of alkali or alkaline earth metal, used in the process for producing salt of formula (II) may be selected from inorganic bases like metallic hydroxides such as but not limited to those of sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide and magnesium hydroxide; metal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate, barium carbonate, calcium carbonate and magnesium carbonate; metal bicarbonate such as sodium bicarbonate, potassium bicarbonate, barium bicarbonate, calcium bicarbonate.

The suitable solvent, used in the process for producing salt of formula (II) may be selected from the group comprising of water; alcohols, such as methanol, ethanol and isopropanol; nitriles, such as acetonitrile; chlorinated hydrocarbons, such as methylene chloride, ethylenedichloride; dipolar aprotic solvents, such as dimethylsulfoxide, dimethyacetamide and dimethylformamide; esters, such as ethyl acetate and isopropyl acetate; cyclic ethers, such as dioxane and tetrahydrofuran; ketone such as acetone, diisobutyl ketone, cyclohexanone, methylcyclohexanone, methyl ethyl ketone, methyl isobutyl ketone, acetylacetone or mixtures thereof.

The process for producing a salt of formula (II) may be carried out by reacting Pralatrexate of formula (I) at a temperature range of 0°C-60°C. Preferably the temperature is between 20-30°C.The process for producing a salt of formula (II) may be carried out by reacting Pralatrexate of formula (I) for about 1 minute to 24 hours. Preferably reaction is carried out for 10 minutes to 8 Hours. A second suitable solvent may be used in the process for producing salt of formula (II) as defined herein above. The reaction mixture may be further cooled in the process for producing salt of formula (II) at a temperature range of -80° to 20°C. The salt of formula (II) may be isolated from the reaction mixture by freeze drying or filtration. The salt of formula (II) may be isolated from the reaction mixture at a temperature range of - 200°C to 30°C.

The Salt of formula (II) may be converted to compound of formula (I).

The process for producing crystalline of salt of formula (IF) may be carried out in an aqueous medium. The crystalline salt of formula (IF) may be obtained by adding a suitable second solvent to the reaction mixture. The second solvent may be selected from methanol, ethanol, 2-propanol, Tetrahydrofuran, acetic acid, acetonitrile and acetone. The process for producing a crystalline salt of formula (IF) may be carried out at a temperature range of 0°C - 60°C. Preferably the temperature is between 20-30°C.

The process for producing a crystalline salt of formula (IF) may be carried out for about 1 minute to 24 hours. Preferably reaction is carried out for 10 minutes to 15 minutes. The reaction mixture may be isolated by filtration to obtain a crystalline salt of formula (Π').

The process for producing an amorphous salt of formula (IF) may be carried out in an aqueous medium.

The process for producing an amorphous salt of formula (IF) may be carried out at a temperature range of 0°C - 60°C. Preferably the temperature is between 20-30°C.

The process for producing an amorphous salt of formula (IF) may be carried out for about 1 minute to 24 hours. Preferably reaction is carried out for 10 minutes to 20 minutes. The amorphous salt of formula (IF) may be obtained by isolating the reaction mixture by freeze drying.

The process for producing an amorphous salt of formula (Ila) may be carried out in a suitable solvent.

The reaction mixture may be cooled in the process for producing salt of formula (Ila) in the temperature range of -80° to 20°C. Preferably the temperature is between -20 to 15°C. The process for producing an amorphous salt of formula (Ila) may be carried out for about 1 minute to 24 hours. Preferably reaction is carried out for 1 hour to 8 hours.

The reaction mixture may be isolated by filtration to obtain amorphous salt of formula (Ila).

The process for producing an amorphous salt of formula (lib) may be carried out in an aqueous medium.

The amorphous salt of formula (lib) may be obtained by adding a suitable second solvent to the reaction mixture. The second solvent may be selected from methanol, ethanol, 2- propanol, Tetrahydrofuran, acetic acid, acetonitrile and acetone.

The process for producing an amorphous salt of formula (lib) may be obtained by cooling the reaction mixture in the temperature range of -25°C to 25°C.

The reaction mixture may be isolated by filtration to obtain a salt of formula (lib).

As used herein the term "isolation" includes filtration, filtration under vacuum, freeze drying, and decantation.

The term "freeze drying" as used herein describes a process in which a solution or slurry containing the salt of formula (IF) is placed within a container and cooled or frozen under vacuum. The container is connected to one or more vacuum sources, and a vacuum (pressure less than 760 torr) is applied. The container is then cooled to a temperature less than 0°C, preferably between -200° C and 0° C.

In further aspect is provided a pharmaceutical composition comprising salts of formula (II) and at least one pharmaceutically acceptable excipient.

In still further aspect further is provided a method for treatment of tumors using pharmaceutical composition comprising salt of formula (II), including both solid tumors and leukemias. The composition may be used in the treatment of human mammary tumors and human lung cancer, particularly in the treatment of T-cell lymphomas. The following examples are provided to illustrate the invention and do not limit the scope thereof. One skilled in the art will appreciate that although specific reagents and conditions are outlined in the following examples, modifications can be made which are meant to be encompassed by the spirit and scope of the invention. Example-1

Pralatrexate

To aqueous sodium hydroxide (11.6 g NaOH in 472 mL water) and Methanol (944 iriL), 10-Propargyl-lO-deazaminopterin dimethyl ester (59.0 g) was added at 20-25°C and stirred the reaction mass for 8 hours. After completion of reaction which was monitored by HPLC, pH of the reaction mass was adjusted to 6.6 with acetic acid. Excess methanol was evaporated under reduced pressure below 40° C and water (1298mL) was added to the residual solution. The pH of the residual solution was adjusted to 4.5 with dilute acetic acid. The reaction mass was stirred for 30 minutes at 20-25° C and precipitated solid was filtered. The solid was furthered purified with water (590 mL) by stirring at 20- 25°C for 30-35 minutes. The solid was filtered and dried under vacuum at 35-40° C to give 39 g (70 %) of the title compound.

Purity: 99.56 %

Water content = 4.8 % (w/w)

*H NMR (DMSO-d6; 400MHz): δ 1.91 (m, IH), 2.05 (m, IH), 2.33 (t, J=7.2 Hz, 2H), 2.59 (bm, 2H), 2.78 (s, IH), 3.14-3.20 (bm, IH), 3.28 (dd, J=14.4 Hz & 6.4 Hz, IH), 3.64 (quintet, J=7.2 Hz), 4.35 (bm, 1H), 6.30 (bs, 2H, NH₂), 7.39 (d, J=8.0 Hz, 2H), 7.61 & 7.63 (2xbs, 2H, NH₂), 7.73 (d, J=8.0Hz, 2H), 8.39 (bs, 1H), 8.50 (d, J=7.6 Hz, 1H, NH), 12.20 (bs, 2H, 2xC0₂H).

¹³C NMR (DMSO-d6; 100MHz): δ 24.84 (CH₂), 25.94 (CH₂), 30.46 (CH₂), 39.08 (CH₂), 43.05 (CH), 51.93 (CH), 72.90 (CH), 82.57 (C), 121.51 (C), 127.35 (2xCH), 127.35 (2xCH), 132.22 (C), 146.69 (C), 147.20 (C), 150.56 (CH), 154.17 (C), 162.41 (C), 162.77 (C), 166.42 & 166.46 (CONH), 173.54 (C0₂H), 173.94 (C0₂H).

MS (ES+) m/z: 478 [M+H]⁺.

IR (KBr, cm^-1): 1540, 1557, 1639, 1704, 3300, 3420.

XRD (°2Theta; Cu): 8.47, 10.85, 12.28, 14.34, 15.00, 15.78, 18.90, 21.79, 24.20, 27.5, 28.92, 34.28.

Example-2

Crystalline Pralatrexate disodium salt

To sodium hydroxide (0.10 g) dissolved in water (12 ml) was added Pralatrexate (0.6 g) at 20-25°C and stirred for 10 min at 20-25°C. Isopropanol (85 ml) was added to the resulting solution and stirred for further 4 hours at 20-25°C. The solid was filtered and dried the solid under vacuum at 35-40°C to give 0.50 g (76.3 %) of the title compound.

Weight : 0.50 g

Yield : 76.3%

Water content : 10.3% w/w

XRD (°20;Cu) : 4.32, 6.08, 6.81, 9.93, 17.4, 23.13, 25.48, 27.82

Example-3

Amorphous Pralatrexate disodium salt

To sodium hydroxide (0.086 g) dissolved in water (5 ml) was added Pralatrexate (0.50 g) at 20-25°C and stirred for 15-20 min at 20-25°C. The resulting reaction mixture was freeze dried under vacuum for 24 hours to give 0.5 g (91.5 %) of the title compound. Weight : 0.50 g

Yield : 91.5 % Water content 8.2 % w/w

XRD (°2Θ; Cu) Halo at 26^c

Example-4

Pralatrexate dilithium salt

To Pralatrexate (2.0 g) in Methanol (20 mL), Lithium hydroxide (0.501 g) was added at 20-25°C and stirred for 5 hours. The reaction mixture was cooled to 0-5°C and the product was filtered. The cooling and filtration was carried out in presence of nitrogen. The filtered product was washed with cold (0-5°C) Methanol (4 mL), suck-dried for 2-3 hours and further dried under vacuum at 50-55°C for 14-18 hours. The product was characterized by XRD, TGA and DSC. Weight : 1.1 g

Yield : 44 %

Purity by HPLC (%) : 99.8

Water content : 1.7 % w/w

Example-5

Pralatrexate dipotassium salt

To Pralatrexate (2.0 g) in Demineralized water (16 mL), aqueous Potassium hydroxide (0.5 g in 4mL Demineralized water) was added at 20-25°C and stirred for 25-30 min. To this agitating reaction mixture, Isopropanol (110 mL) was added. The reaction mixture was stored at -20 to -15°C for 12 hours and then was allowed to warm to 0-5°C with stirring. The product was filtered, washed with Isopropanol (10 mL), suck-dried for 1-2 hours followed by drying at 50-55°C for 8 hours. The product was characterized by XRD, TGA and DSC. Weight 1.7 g Yield 73.9 %

Purity by HPLC 99.8 % Water content 1.7 % w/w

Claims

1. A salt of Pralatrexate of formula (II)

wherein M is an alkali or alkaline earth metal selected from the group comprising of sodium, potassium, lithium, calcium and magnesium.

2. The salt of claim 1, wherein M is sodium.

3. The salt of claim 2, wherein the salt is crystalline characterized by X-ray diffraction pattern with peaks at about 4.32, 6.08, 6.81, 9.93, 17.4, 23.13, 25.48, 27.82 ± 0.2°two-theta.

4. The salt of claim 2, wherein the salt is in amorphous form.

5. The salt of claim 1, wherein M is lithium.

6. The salt of claim 5 wherein the salt is in amorphous form.

7. The salt of claim 1 wherein M is potassium.

8. The salt of claim 7 wherein the salt is in amorphous form.

9. A process for preparing a salt of Pralatrexate of formula (II) comprising the steps of a) reacting Pralatrexate of formula (I)

with a source of alkali or alkaline earth metal in a suitable solvent to obtain a reaction mixture;

b) stirring the reaction mixture of step (a) and;

c) isolating the salt from the reaction mixture.

10. A process of claim 9 wherein the source of alkali metal of step (a) is selected from the group comprising of sodium hydroxide, potassium hydroxide, lithium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate.

11. A process of claim 9 wherein step (a) is optionally followed by addition of a second suitable solvent.

12. A process of claim 9 or claim 11 wherein the suitable solvent is selected from the group comprising of water, methanol, ethanol, isopropanol, acetonitrile, methylene chloride, ethylenedichloride, dimethylsulf oxide, dimethyacetamide and dimethylformamide, ethyl acetate, isopropyl acetate, dioxane, tetrahydrofuran, acetone, diisobutyl ketone, cyclohexanone, methylcyclohexanone, methyl ethyl ketone, methyl isobutyl ketone, acetylacetone.

13. A process of claim 9 wherein step (b) is optionally followed by cooling.

14. A process of claim 13 wherein the said cooling is from - 80°C to 20°C.

15. A process of claim 9 wherein salt of step (c) is isolated by freeze drying or filtration.

16. A pharmaceutical composition comprising a salt of claim 1 and at least one pharmaceutically acceptable excipient.

17. A method of treating tumors using pharmaceutical composition comprising a salt of Pralatrexate of claim 1.